Coronary syndrome X is frequently observed among perimenopausal and postmenopausal women and the chest pain is sometimes relieved by estrogen replacement therapy (ERT).In our previous studies, we report that coronary capillary network in middle-aged females is regulated by physiologic angiogenesis of VEGF, and that reduction in coronary VEGF expression by estrogen deficiency could play a role as a molecular pathogenesis in the development of coronary heart disease in postmenopausal women.In our next series of studies, we demonstrated that estrogen receptors especially estrogen receptor alpha plays crucial role in maintaining coronary microcirculation and vascular endothelial growth factor (VEGF) signaling in female heart.In our series of studies, we found that loss of VEGF from early diabetes is the initial trigger for all the structural and functional changes responsible for diabetic retinopathy.In this present study, we tried to clarify how estrogen/estrogen receptor affects coronary VEGF signaling in diabetic model.We found that, VEGF angiogenic signaling is much more decreased in ovariectomized female rat heart in presence of diabetes compared to the absence of diabetes which has direct correlation with the functional impairment of heart.There is great imbalance between VEGF and the soluble forms of VEGF receptors in female heart in the states of ovariectomy, diabetes or in ovariectomized diabetic condition.Estrogen replacement is partially effective in normalizing impaired/downregulated VEGF angiogenic signaling in female heart in ovariectomized rats in presence or absence of diabetes.The induction of diabetes in ERαKO female mice has more detrimental downregulation of cardiac VEGF angiogenic signaling compared to ERαKO mice without diabetes.Whereas, the streptozotocin administration in ERβKO female mice could not further worsen the VEGF angiogenic signaling in heart compared to ERβKO female mice heart without diabetes.Diabetes induction in ERαKO female mice has further worsened the cardiac function compared to ERαKO mice without diabetes.This cardiac functional impairment has not been clearly evident in streptozotocin administered ERβKO female mice compared to ERβKO female mice heart without diabetes.